Abstract Most somatic cells accumulate molecular damage with aging, leading to the development of cellular senescence, defined as cell cycle arrest and the development of a proinflammatory `senescence-associated secretory phenotype' (SASP). Thus, with increasing age, cells with varying degrees of senescence accumulate in tissues. While some cell populations in the brain (e.g. neurons) become post-mitotic early during development, others (e.g. glia) preserve the capacity for mitosis and for bona fide senescence. Senescent astrocytes as well as neurons displaying senescent-like changes accumulate in the aging brain, and this is exacerbated in Alzheimer's disease (AD). The premise of the present studies is that cellular senescence/SASP generates a tissue environment primed to sustain diseases of aging. Inflammation is mechanistically involved in the pathogenesis of AD. While microglia and astrocytes have been implicated in AD inflammation, age-associated inflammation is due in part to increased numbers of SASP- producing senescent cells. Whether the accumulation of senescent cells in brain has a mechanistic role in AD, however, is unknown. Studies from our laboratories and others have shown that attenuation of the mammalian target of rapamycin (mTOR) potently blocks cellular senescence and SASP. Systemic mTOR attenuation also extends lifespan and healthspan in mice, and blocks AD-like progression in four different models of AD. Similarly, the elimination of senescent cells recapitulates the effects of mTOR inhibition on lifespan, improving tissue function, delaying age-related pathologies, and extending longevity in mice. Whether cell senescence/SASP contributes to the pathogenesis of AD is still unknown. Our central hypothesis is that brain cellular senescence contributes to AD-like pathogenesis in AD model mice in a manner dependent on mTOR. To test this hypothesis, we propose three Specific Aims. In Aim 1, we will ablate senescent cells systemically in a mouse model of AD using genetic tools (p16-3MR mice) and with senolytics (drugs that selectively kill senescent cells), and determine the impact on AD-relevant outcomes. In Aim 2, we will eliminate senescent astrocytes in hippocampi of AD model mice, and determine impact on synaptic, histopathological and cognitive AD-relevant outcomes. In Aim 3, we will overactivate mTOR in hippocampal astrocytes of AD mice in the presence or absence of the same senolytics as in Aim 1, and determine effects on AD-relevant outcomes. If our hypothesis is validated, this work will be significant because it will (a) define the contribution of cellular senescence/SASP to AD, and (b) define the role of mTOR in brain cellular senescence. By singling out cellular senescence as a novel mechanism of AD-like pathogenesis in mice, we will open up a completely new avenue of investigation in AD. Furthermore, because the senolytic drugs we will use are FDA- approved, our results may be rapidly translated, contributing new and urgently needed approaches to prevent or treat AD and potentially other age-related brain pathologies.